Stroke is the largest cause of adult disability worldwide. The incidence of stroke is about 1.3% of the US population, and 39.4% of victims show significant residual impairments, ranging from hemiplegia to restricted limb use and speech defects. Approximately 60% of strokes are caused by occlusion of the middle cerebral artery (MCAo), resulting in damage in the striatum and cortex with consequent deficits to sensory and motor systems. There is therefore a substantial clinical need for treatments that reduce or alleviate the deficits.
Typical therapies for stroke are aimed at interrupting the cascade of events that lead to intraneuronal calcium accumulation and cell death, and to provide stimulation through rehabilitation, e.g. physiotherapy, to promote intracerebral reorganisation. However, pharmacological treatments must be administered quickly to protect against cell death that typically occurs within three hours of occlusion. In addition, the therapy based on rehabilitation appears to be limited to a period of 3-6 months after stroke, after which residual disabilities do not undergo appreciable reduction.
There has been much interest recently in the possibility of transplanting new cells into the damaged neuronal system to promote repair and alleviate the disorders. One difficulty associated with cell transplantation is the need to provide clonal cell lines from different regions of the brain. This has proved to be a major difficulty in preparing cells for transplantation. WO-A-97/10329 describes the use of conditionally immortalised pluripotent neuroepithelial cells in the transplantation into the damaged brain. The neuroepithelial cells express a temperature-sensitive oncogene so that they are capable of unlimited expansion under permissive low temperatures in vitro, but cease dividing to develop into mature neural cells on implantation into the higher temperature of the brain (38° C.). A particular advantage of these cells has been shown to be their ability to develop into site-appropriate neurons or glia, under the control of signals from the host brain, so that problems associated with choosing the correct tissue for transplantation is avoided. It has also been shown that the cells can migrate to the site of damage when transplanted into a region proximal to the damaged site. Therefore, the use of these cells offers a viable alternative to pharmacological treatments for repair of brain damage.
However, although the cells were shown to migrate to discrete areas of damage, focal ischaemia results in extensive damage and it is by no means certain that areas of infarction would provide a sufficiently well vascularised matrix to support the survival of grafted cells.
There is therefore the need for improvements in transplantation in order to provide cells that successfully graft into the adult damaged brain and compensate for the deficits.